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    ABSTRACT: Oncofoetal antigens are present during foetal development with generally limited expression in the adult but are upregulated in cancer. These molecules can sometimes be used to diagnose or follow treatment of tumours or as a target for different immunotherapies. The 5T4 oncofoetal glycoprotein was identified by searching for shared surface molecules of human trophoblast and cancer cells with the rationale that they may function to allow survival of the foetus as a semi-allograft in the mother or a tumour in its host, potentially influencing growth, invasion or altered immune surveillance of the host. 5T4 tumour selective expression has stimulated the development of 5T4 vaccine, 5T4 antibody targeted-superantigen and 5T4 antibody-drug therapies through preclinical and into clinical studies. It is now apparent that 5T4 expression is a marker of the use (or not) of several cellular pathways relevant to tumour growth and spread. Thus 5T4 expression is mechanistically associated with the directional movement of cells through epithelial mesenchymal transition, facilitation of CXCL12/CXCR4 chemotaxis, blocking of canonical Wnt/beta-catenin while favouring non-canonical pathway signalling. These processes are highly regulated in development and in normal adult tissues but can contribute to the spread of cancer cells. Understanding the differential impact of these pathways marked by 5T4 can potentially improve existing, or aid development of novel cancer treatment strategies.
    Seminars in Cancer Biology 07/2014; 29. DOI:10.1016/j.semcancer.2014.07.004
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    ABSTRACT: Receptor tyrosine kinase pathways are potential therapeutic targets in gastric adenocarcinoma patients. We evaluated HER2 and cMet protein expression, and FGFR2 gene amplification to assess their prognostic significance, and downstream mediators pS6 and pERK for their potential utility as pharmacodynamic biomarkers in patients with gastric adenocarcinoma. Tissue microarrays were constructed from resection samples of 184 patients who underwent surgery for gastric/gastro-oesophageal junction adenocarcinoma. Tissue cores were obtained from the tumour body (TB), luminal surface (LS) and invasive edge (IE), and immunohistochemical and fluorescence in situ hybridisation (FGFR2) analysis was performed. FGFR2 amplification was identified in 2 % of cases and associated with worse survival (P = 0.005). HER2 overexpression was observed in 10 % of cases and associated with increased survival (P = 0.041). cMet overexpression was observed in 4 % of cases and associated with worse survival (P < 0.001). On multivariate analysis, only cMet retained significance (P = 0.006). pS6 and pERK expression were observed in 73 % and 30 % of tumours, respectively, with no association with survival. HER2 (P = 0.004) and pERK (P = 0.001) expression differed between tumour regions with HER2 expression increased in the LS compared with the TB and IE. These findings confirm subpopulations in gastric adenocarcinoma with poor outcome that may benefit from specific therapeutic strategies. However, we found heterogeneous HER2, pS6 and pERK overexpression, which presents challenges for their use as predictive biomarkers in gastric biopsies. The potential downstream pharmacodynamic markers pS6 and pERK were expressed across tumour regions, providing evidence that resections and biopsies would yield comparative results in clinical trials.
    Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin 12/2013; 464(2). DOI:10.1007/s00428-013-1517-y
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    ABSTRACT: In chronic myeloid leukaemia, (CML), cells from different stages of maturation may have differential expression of BCR-ABL at both mRNA and protein level. However, the significance of such differential expression to clinical disease behaviour is unknown. Using the CML-derived, BCR-ABL expressing cell line, K562, distinct plastic-adherent (K562/Adh) and non-adherent (K562/NonAdh) sub-populations were established then analysed both as single cells and as bulk cell populations. BCR-ABL mRNA was up-regulated in K562/Adh compared to K562/NonAdh cells in both single cell and bulk population analyses (p<0.0001). Similarly, phosphorylation of BCR protein was up-regulated in K562/Adh, compared to K562/NonAdh cells (63.42% vs 23.1%, p=0.007), and these two K562 sub-populations were found to express significantly different miRNA species. Furthermore, treatment with the BCR-ABL tyrosine kinase inhibitor, imatinib, reduced cell viability more rapidly in K562/NonAdh compared to K562/Adh cells (p<0.005) both at single and bulk cell levels. This discovery of an adherent sub-population of K562 cells with increased BCR-ABL mRNA, increased phosphorylated BCR protein expression, differential miRNA expression, and increased imatinib resistance, suggests a similar sub-population of cells may also mediate clinical resistance to imatinib during treatment of CML patients.
    Experimental hematology 11/2013; 42(3). DOI:10.1016/j.exphem.2013.11.006
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    ABSTRACT: Background: Both gemcitabine and bexarotene are established single agents for the treatment of cutaneous T-cell lymphoma (CTCL). We investigated the feasibility and efficacy of combining these drugs in a single-arm phase II study. Methods: Cutaneous T-cell lymphoma patients who had failed standard skin-directed therapy and at least one prior systemic therapy were given four cycles of gemcitabine and concurrent bexarotene for 12 weeks. Responders were continued on bexarotene maintenance until disease progression or unacceptable toxicity. Results: The median age was 65 years, stage IB (n=5), stage IIA (n=2), stage IIB (n=8), stage III (n=8) and stage IVA (n=12), 17 patients were erythrodermic, 17 patients were B1, and 10 patients were both erythrodermic and B1. Thirty (86%) patients completed four cycles of gemcitabine. In all, 80.0% of patients demonstrated a reduction in modified Severity-Weighted Assessment Tool (mSWAT) score although the objective disease response rate at 12 weeks was 31% (partial response (PR) 31%) and at 24 weeks 14% (PR 14%, stable disease (SD) 23%, progressive disease (PD) 54%, not evaluable 9%). Median progression-free survival was 5.3 months and median overall survival was 21.2 months. Conclusion: The overall response rate of the combination did not reach the specified target to proceed further and is lower than that previously reported for gemcitabine as a single agent.
    British Journal of Cancer 10/2013; 109(10). DOI:10.1038/bjc.2013.616
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    ABSTRACT: Non-small cell lung cancer (NSCLC) accounts for >80% of lung cancer cases and currently has an overall five-year survival rate of only 15%. Patients presenting with advanced stage NSCLC die within 18-months of diagnosis. Metastatic spread accounts for >70% of these deaths. Thus elucidation of the mechanistic basis of NSCLC-metastasis has potential to impact on patient quality of life and survival. Research on NSCLC metastasis has recently expanded to include non-cancer cell components of tumors-the stromal cellular compartment and extra-cellular matrix components comprising the tumor-microenvironment. Metastasis (from initial primary tumor growth through angiogenesis, intravasation, survival in the bloodstream, extravasation and metastatic growth) is an inefficient process and few released cancer cells complete the entire process. Micro-environmental interactions assist each of these steps and discovery of the mechanisms by which tumor cells co-operate with the micro-environment are uncovering key molecules providing either biomarkers or potential drug targets. The major sites of NSCLC metastasis are brain, bone, adrenal gland and the liver. The mechanistic basis of this tissue-tropism is beginning to be elucidated offering the potential to target stromal components of these tissues thus targeting therapy to the tissues affected. This review covers the principal steps involved in tumor metastasis. The role of cell-cell interactions, ECM remodeling and autocrine/paracrine signaling interactions between tumor cells and the surrounding stroma is discussed. The mechanistic basis of lung cancer metastasis to specific organs is also described. The signaling mechanisms outlined have potential to act as future drug targets minimizing lung cancer metastatic spread and morbidity.
    Cancer Treatment Reviews 10/2013; 40(4). DOI:10.1016/j.ctrv.2013.10.001
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    ABSTRACT: The European Network for Breast Development and Cancer (ENBDC) Workshop on 'Methods in Mammary Gland Development and Cancer' has grown into the essential, international technical discussion forum for scientists with interests in the normal and neoplastic breast. The fifth ENBDC meeting was held in Weggis, Switzerland in April, 2013, and focussed on emerging, state-of-the-art techniques for the study of non-coding RNA, lineage tracing, tumor heterogeneity, metastasis and metabolism.
    Breast cancer research: BCR 10/2013; 15(5):313. DOI:10.1186/bcr3497
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    ABSTRACT: Although survival from breast cancer has improved significantly over the past 20 years, disease recurrence remains a significant clinical problem. The concept of stem-like cells in cancer has been gaining currency over the last decade or so, since evidence for stem cell activity in human leukaemia and solid tumours, including breast cancer, was first published. Evidence indicates that this sub-population of cells, known as cancer stem-like cells (CSCs), is responsible for driving tumour formation and disease progression. In breast cancer, there is good evidence that CSCs are intrinsically resistant to conventional chemo-, radio- and endocrine therapies. By evading the effects of these treatments, CSCs are held culpable for disease recurrence. Hence, in order to improve treatment there is a need to develop CSC-targeted therapies. Interleukin-8 (IL-8), an inflammatory cytokine, is upregulated in breast cancer and associated with poor prognostic factors. Accumulating evidence demonstrates that IL-8, through its receptors CXCR1/2, is an important regulator of breast CSC activity. Inhibiting CXCR1/2 signalling has proved efficacious in pre-clinical models of breast cancer providing a good rationale for targeting CXCR1/2 clinically. Here, we discuss the role of IL-8 in breast CSC regulation and development of novel therapies to target CXCR1/2 signalling in breast cancer.
    Expert Opinion on Therapeutic Targets 09/2013; 17(11). DOI:10.1517/14728222.2013.835398
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    ABSTRACT: Angiogenesis has been validated as a target in ovarian cancer through four randomized trials that have reported improved progression-free survival (PFS) in patients with ovarian cancer whose conventional treatment was supplemented with concurrent and maintenance administration of the antivascular endothelial growth factor (VEGF) antibody, bevacizumab. These trials [the International Collaborative Ovarian Neoplasm Group trial (ICON7), the Gynecologic Oncology Group trial (GOG218), OCEANS and AURELIA] have shown that the tumour vasculature is a valid target throughout the lifetime of patients with ovarian cancer. This review seeks to address some of the remaining questions surrounding the optimal strategy for the use of bevacizumab in ovarian cancer. The first-line trials, ICON7 and GOG218, showed improvements in PFS and in the case of ICON7, an early analysis reported increased overall survival in a predefined group of patients at high risk of disease progression. Trials in recurrent disease, OCEANS and AURELIA, also showed improvements in PFS, raising questions about whether VEGF-inhibiting agents should be confined to first-line therapy, second-line therapy or both. Both the first-line trials stopped maintenance bevacizumab after 12 and 15 months, respectively; yet, current data suggest that maintenance therapy should continue at least until progression. In addition, current research is focussing on the identification of predictive biomarkers for VEGF inhibitors and candidates have been identified. Thus, the true clinical benefit from VEGF pathway inhibitors in the first-line treatment of ovarian cancer is likely to increase over the next few years.
    Current opinion in oncology 09/2013; 25(5):558-65. DOI:10.1097/CCO.0b013e328363e0da
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    ABSTRACT: Breast cancer stem-like cells (CSCs) are an important therapeutic target as they are purported to be responsible for tumor initiation, maintenance, metastases, and disease recurrence. Interleukin-8 (IL-8) is upregulated in breast cancer compared with normal breast tissue and is associated with poor prognosis. IL-8 is reported to promote breast cancer progression by increasing cell invasion, angiogenesis, and metastases and is upregulated in HER2-positive cancers. Recently, we and others have established that IL-8 via its cognate receptors, CXCR1 and CXCR2, is also involved in regulating breast CSC activity. Our work demonstrates that in metastatic breast CSCs, CXCR1/2 signals via transactivation of HER2. Given the importance of HER2 in breast cancer and in regulating CSC activity, a pathway driving the activation of these receptors would have important biological and clinical consequences, especially in tumors that express high levels of IL-8 and other CXCR1/2-activating ligands. Here, we review the IL-8 signaling pathway and the role of HER2 in maintaining an IL-8 inflammatory loop and discuss the potential of combining CXCR1/2 inhibitors with other treatments such as HER2-targeted therapy as a novel approach to eliminate CSCs and improve patient survival.
    Breast cancer research: BCR 08/2013; 15(4):210. DOI:10.1186/bcr3436
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    Cell cycle (Georgetown, Tex.) 08/2013; 12(18). DOI:10.4161/cc.26280
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Journal of Pharmaceutical Sciences 04/2013; 102(4). DOI:10.1002/jps.23458
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